Background <p>Intractable or drug-resistant epilepsy is a condition in which seizures cannot be adequately controlled with antiepileptic medications. When resective surgery is not feasible or ineffective, neuromodulation therapy, such as the vagus nerve stimulation (VNS), represents a safe and approved treatment alternative. Nonetheless, the extent of its clinical benefit remains incompletely characterized. This systematic review and meta-analysis were conducted to evaluate the clinical benefit and treatment response of invasive VNS in reducing seizure frequency among patients with intractable epilepsy.</p> Results <p>Four databases (PubMed/MEDLINE, Embase/Scopus, Cochrane, and Web of Science databases) were searched from database inception through November 2024. Data analysis was performed with Review Manager (RevMan 5.4), using a random-effect model based on heterogeneity. Five cohort studies (three prospective and two retrospective) were included in the quantitative analysis, involving 244 participants with intractable epilepsy. The pooled analysis revealed a statistically significant association between VNS and reduced seizure occurrence compared with baseline (RR = 0.57, 95% CI = 0.36–0.91). Adverse events, reported in three studies, were generally mild to moderate. Two studies assessing the relationship between seizure type and VNS response consistently demonstrated a more favorable response in patients with generalized epilepsy. One study reported a positive response to VNS therapy in patients with prior surgery in the focal resection group (&gt; 60%), followed by corpus callosotomy (33%). However, none of the studies reported a significant reduction in antiseizure medication use following VNS therapy.</p> Conclusion <p>VNS was associated with reduced seizure occurrence in patients with intractable epilepsy, supporting its potential role as a neuromodulatory treatment option, notably in generalized epilepsy.</p>